The cause of MS is unknown, there is no cure, and the current therapies have limited efficacy. My laboratory focuses on identifying molecules critical to the pathogenicity of encephalitogenic T cells. Since the CNS is an immune-privileged tissue and immunological surveillance is limited, we hypothesize that encephalitogenic T cells express unique molecules that enhance their encephalitogenic capacity and that these molecules may be therapeutic targets for MS. In experimental autoimmune encephalomyelitis (EAE), a model of MS, myelin-specific Th1 and Th17 can induce disease. However, we also know that not all myelin-specific Th1 and Th17 cells induce disease, suggesting that expression of pro-inflammatory cytokines by myelin-specific T cells is not sufficient to deem a myelin-specific T cell encephalitogenic. In the proposed study, we will identify molecules that distinguish encephalitogenic and non- encephalitogenic myelin-specific Th1 and Th17 cells and analyze the role of these molecules in EAE and MS. Specific Aim 1: Identify molecules differentially expressed in encephalitogenic and less-encephalitogenic myelin-specific Th1 cells that contribute to T cell pathogenicity. Specific Aim 2: Identify molecules differentially expressed in encephalitogenic and non-encephalitogenic myelin- specific Th17 cells that contribute to T cell pathogenicity. Identification of molecules critical for disease has largely been done by gene knockout studies. However, these studies give limited information on the role of the molecule in disease and many knockout studies have yielded surprising phenotypes. Using differential expression in very specific and closely related T cell populations, we should be able to identify several molecules that are clearly associated with encephalitogenicity and determine molecular pathways that are critical for this process. These molecules would provide targets for the development of new therapeutic agents for MS. PUBLIC HEALTH RELEVANCE: Project Narrative Multiple Sclerosis (MS) is an immune-mediated disease that destroys the myelin sheath around axons, resulting in impaired nerve conduction and functional loss. Since the cause of MS is unknown, there is no cure, and current therapies are only partially affective. Approximately 350,000 Americans live with MS and many will become physically handicapped during their lifetime. The current study focuses on identifying unique to the immune cells that damage the myelin, so that new therapeutic agents can be developed for MS and other immune-mediated diseases.